Parkinsonism & Related disorders 2016 jan

1. Parkinsonism & Related Disorder
2016 vol 22 (一月號)
Medical Scientific Liaison, MSL
Willy Wen,文偉立
GSK Neuroscience (2012~)
Taipei Medical University
Pharmacy (2006-2009)

2. Highlights
•Patients with Parkinson's disease (PD) may develop several non-motor symptoms.
•Rapid eye movement sleep behavior disorder (RBD) is commonly associated with
PD.
•RBD may have associations with visual hallucinations (VH) and cognitive
impairment (CI).
•Presence of either VH or CI may be a risk factor for development of the other.
•Interactions of VH, RBD and CI may have important clinical significance.

3. Evidence from
•Clinical and epidemiological
studies
•Neuroimaging studies
•Cholinergic dysfunction
•Synucleinopathies

4. 爭點1: RBD and VH in PD: a continuum or two
distinct phenomena? Cont’d
1. Degeneration of process: (continuum)
• REM, RBD to the Braak stage 2,3.
• VH to the Braak stage 6.
• Cognitive impairment in PD to the Braak stage 4,5,6.
2. Evidence from clinical and epidemiological studies (High prevelence,2 y/o)
• Vivid dreams and nightmares found in RBD and PD.(Pappert 1999) Double frequency in PD with
RBD.(Gjerstad 2008) Higher risk of emergence of VH in PD with RBD after 2 year follow-
up.(Sinforiani 20008)
• RBDSQ score of ≥6: 38% of PD with RBD develop VH at follow up 2 years, whereas none of PD
w/o RBD. (Poryazoya 2013)
• Polysomnography: Reduced sleep efficiency, total REM sleep duration, and REM sleep
percentage in PD with VH. (Comella 1993)
3. Evidence from neuroimaging studies (GM atrophy but not overlap that much)
• iRBD: reduced gray matter volume, as thalamus (Salons 2014), putamen (Ellmore 2010),
cerebellum tegmental portion of pons and parahippocampal regions (Hanyu 2012)
• PD with VH: GM atrophy in dorsal and ventral visual pathways (Goldman 2014), frontal
regions (Watanabe 2013), limbic regions and hippocampus (Ibarretxe-Bilbao 2010; Ibarretxe-
Bilbao 2008).

5. 爭點1: RBD and VH in PD: a continuum or two
distinct phenomena? Cont’d
1. Evidence from cholinergic dysfunction (Be seen in RBD,VH, CI in PD)
• Short latency afferent inhibitoin by TMS.
• Nardone et al N=23 PD, (with RBD 10; w/o 13)
• Managanelli et al, N=22 PD (with VH 10; w/o 12)
2. Neuropsychological evaluation (highly associated, but need robust studies)
• Deficits in visuo-spatial learning, executive function and verbal memory in both
“PD with RBD or VH” and “iRBD”. (Ferini-Stramni 2004; Massicotte-Marquez
2008)
• It may be: the emergence of RBD and VH in PD association with visuoperceptive
functions.

6. 爭點2: VH and CI in PD: does one
predict the other?
1. Evidence from the clinical and epidemiological studies (high coexsist)
• PD=45, 24 with VH & 21 w/o VH (Ramirez-Ruiz 2007)
• 45% with VH developed MCI
• With VH 82%, compare to w/o VH 30% .
• Impairments in verbal memory and attention (Hepp 2013).
• VH is a Risk factors for dementia in PD, follow-up 4.4 years with 34% (Anang 2014).
• CALM-PD trial (n=301), lower MMSE at baseline to develop hallucination (Biglan
2007).
2. Evidence from neuroimaging studies (overlapping)
• Hippocampal and para-hippocampal atrophy.
• Lingual gyrus, posterior cingulate gyrus .

7. 爭點3 : RBD and CI in PD: a tug of war between
causation and association?
1. Evidence from clinical and epidemiological studies. (RBD is earlier)
• RBD had impaired episodic verbal memory, executive functions, visuoperceptual
functions. (Vendtte 2007)
• Higher prevalence of MCI in patients with iRBD (50%) , or PD with RBD(73%) , PD
w/p RBD (11%) and Control (8%)(Gagnon 2009)
• 4 Year follow up, 48% of PD with RBD development dementia compare to PD w/o
RBD. (Postuma 2012)
2. Role of cholinergic dysfunction (close association)
• Reported cholinergic dysfunctions in VH, RBD, and PDD.

8. PubMed and PsycINFO database from the year 1995 to July 2015

9. Reminding: IF detect one, figure others two.
10-item self rated
RBDSQ
MMSE

10. Highlights
•Hedonic range for olfactory perception is severely reduced in PD.
•Complex olfactory impairment in PD consists of hyposmia and reduced
hedonic perception.
•Reduced hedonic olfactory perception correlates with anhedonia but not
with global depression in PD.
確認PD depression 是否跟 嗅覺喪失有關聯

11. Aromatic testing: 22 compounds
PleasantUn-Pleasant

12. Highlights
•A total of 31 non-demented PD patients and 20 age-matched controls were studied.
•Patients were sub-classified into groups of PD with mild cognitive impairment (PD-
MCI) and cognitively normal PD (PD-CN).
•The degree of hyposmia self-awareness was calculated as the difference between
subjective and objective olfactory impairment.
•PD-MCI patients tended to rate their olfactory function higher on the olfactory
questionnaire than PD-CN group.
•The loss of awareness of hyposmia is closely associated with mild cognitive
impairment in PD patients.
cognitive impairment (PD-MCI); cognitively normal (PD-CN)
I. Kawasaki et al. / Parkinsonism and Related Disorders 22 (2016) 74e79

13. If PD with MCI, they cannot detect their
olfactory deficit.
Fig. 2. Mean olfactory deficit unawareness
score. PD-MCI, Parkinson's disease with
mild cognitive impairment; PD-CN,
Parkinson's disease and cognitively normal;
HC,
healthy controls. The error bars represent
the standard errors of the means (SEMs).
Asterisks denote **p < 0.01 and ***p <
0.001.
I. Kawasaki et al. / Parkinsonism and Related Disorders 22 (2016) 74e79
cognitive impairment (PD-MCI); cognitively normal (PD-CN)

14. Highlights
•We conducted a door-to-door survey to investigate the ET and its NMS in
Shanghai.
•The prevalence of ET in individuals (≥50 years old) was 0.306%.
•The prevalence of ET in a rural area of Shanghai China is low.
•ET patients had a lower MMSE score compared with the healthy controls.
•Prevalence of certain NMSs was higher among ET patients.
Ethnic?

15. Study populations
1. 1-day workshop to train local doctors in Malu
2. The 9-question screening instrument. (Yes/No)
1. sustained bilateral arm extension
2. bilateral finger-nose-finger maneuver
3. drawing spirals with both the dominant and non-dominant arms.
3. Tremor severity was assessed using the Fahn-Tolosa-Marin essential tremor rating
scale (FTMRS).
Northwestern Shanghai, and Only the residents aged 50 and above were recruited.
Step 1: Train Local Doctor
Step 2: movement disorder
specialists

17. When ET compare to
Health control
Single Question Screening
Restless legs symptoms (Ondo 2006)
Depression** (not significant)
HAMD might not uesful
Olfactory Impairment not present
in ET

18. Highlights
•Motor complications affected over 50% in the first 5 years of Parkinson's disease.
•Dopamine depletion is indicated as an important cause.
•Early levodopa treatment was not associated with motor complications.
•Motor complications were mild in the majority and reversible in more than 35%.
•No patients required advanced treatment during the first 5 years after diagnosis.
Actual L-dopa dose > Initial treatment with L-dopa
drug-naïve Parkinson's disease

19. Demographic at baseline of stduy
• 36/189 never use L-dopa
– 5 (13.9%) motor fluctuation
– 4 (11.1%) dyskinesia
• Levodopa treated group
– 49.7 % motor fluctuation
– 27.5 % dyskinesia
• Risk of develop Motor complication
– MF, HR 1.84 p=0.023 (only)
– Dysknesia, HR 0.88 p=0.744

20. Prevelence and cumulative rate follow
up 5 years
Severity of Motor complications
• Severe MF ≤5.1 %
• Severe dyskinesia ≤ 0.6%
• Painful dyskinesia ≤ 1.8%
Reversal of Dyskinesia (39/158)
• 19 of 39 (49%) had no dysknesia at final
visit
• Patient with persistent motor flucutation
were Younger.

21. Baseline Risk factors for dyskinesia
• Female ;
• Higher baseline UPDRS motor
Baseline Risk factors for motor
fluctuations
• Lower age
• Higher baseline UPDRS motor
BW HR 0.99 p=0.239

22. Highlights
•CuPiD's Smartphone-delivered gait training system is feasible for at-home use
in PD.
•Gait improvements were found after 6 weeks of training and retained 4 weeks
later.
•The CuPiD-system was equally effective for gait training as standard
physiotherapy.
•PD people's balance improved more after training with than without the
CuPiD-system.
combined with a smartphone application (CuPiD-system)

23. CuPiD systemthe audiobiofeedback (ABF-gait app) The FOGtraining (FOG-cue app)
Figure 1.
2A illustrates the CuPiD system with the foot-mounted IMUs and the single large touchscreen button on the smartphone; 2B
shows a schematic overview of the ABF-gait app with at the top a recording of a clinical optimal reference walk, which was
captured under the therapist's supervision. The median value is then used as the reference value (full horizontal line). The pre-set
therapeutic window (dotted horizontal lines) are the percentages above and below the reference value as determined by the
therapist.

25. 電信管制射頻器材管理辦法
1. 大哥大無線手機進口時應檢附那些證件，又該證件應向那個單位申請？
答: 進口大哥大無線手機應檢附電信管制射頻器材進口許可證，該證件應向國家
通訊傳播委員會（NCC）申請。
五、為簡化民眾得攜帶自用之無線電信終端設備及低功率射頻電機進口之管制程
序，增訂郵寄進口二部以內者或自行攜帶進口五部以內之器材，得免請領進
口許可證，並刪除不需電臺執照之電信管制射頻器材為供自用應辦理審驗之
規定。（修正條文第十八條及第十九條）

26. •Visual and auditory cueing improve functional performance in Parkinson's disease (PD)
but need attention-dependent process.
•TC may be processed faster, with minimal attentional demand investigate the efficacy
and limitations of TC for modulating simple (heel tapping) and more complex (walking)
motor tasks.
•simple (seated heel tapping) & complex (straight linewalking with or without a
secondary motor task + holding a tray with two cups of water.
•Baseline gait parameters established in three 15-min walking line

27. Step 1: pre-synchronization
Heel tapping 30 times
With preferred condense
Step 2: Synchronization
Heel tapping with TC condense
and 30 times
Step 3: Continuation
Heel tapping w/o TC but follow
the previous TC condense
Experiment 2
Walking 150 m 4 m hallway
Experiment 1
Heel Tapping
Step 1: pre-synchronization
With preferred condense
Step 2: Synchronization
with TC condense and 30 times
Step 3: Continuation
w/o TC but follow the previous
TC condense

28. A,B: Heel tapping. C,D Waling 15-m
line
第二次有跟拍
第二次快拍

29. Highlights
•PD and healthy controls modulated heel tapping and walking in response to TC.
•Healthy controls modulated walking at slower, comfortable, and 10% faster pace.
•PD patients modulated walking at slower and comfortable pace.
•Secondary motor task slowed down cued heel tapping, but not walking.
•TC effectiveness in increasingly challenging tasks warrants further investigation.

30. Highlights
•A single session of bilateral motor cortical LF rTMS has no effect on LID.
•Multiple bilateral motor cortical LF rTMS sessions are not a good treatment for
LID.
•Bilateral motor cortical LF rTMS sessions are well tolerated in Parkinson
patients.
Insight:
levodopa-induced dyskinesias can benefit from bilateral
subthalamic deep brain stimulation (DBS)
(LF rTMS)

31. LF rTMS failed to treat Levodopa-
induced dyskinesia.
the first study
Unfortunately, bilateral LF rTMS of
the MC is not a suitable treatment
for levodopa-induced dyskinesias in
late-stage
Parkinson patients.
It contrast with previous study
(Brusa 2006;Koch 2005)

32. Highlights
•We compared after-effects following locomotor adaptation in Parkinson's disease.
•Participants with and without freezing of gait were included.
•Magnitude of after-effects were smaller in the freezer group.
•After-effects were similar between controls and the non-freezer group.
•People who freeze may have less storage of adapted locomotor patterns.
freezers (PDtFOG); non-freezers (PD-FOG)
15min on a motor driven rotating disc
S.T. Nemanich, G.M. Earhart / Parkinsonism and Related Disorders 22 (2016) 93e97

33. Split-Belt Walking
Mohammadi et al showed a similar maladaptive response during
split-belt walking, noting a significantly slower adaptation rate in
PD+FOG compared to PD-FOG and controls

34. S.T. Nemanich, G.M. Earhart / Parkinsonism and Related Disorders 22 (2016) 93e97

35. Highlights
•The heritable component of Multiple System Atrophy (MSA) is currently
unknown.
•We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable
component of MSA due to common coding variability.
•We estimate the heritability of MSA in pooled cases at 2.09–6.65%.
•Common genetic variation appears to play a less prominent role in risk for MSA
than in other complex neurodegenerative diseases
Using GWAS

36. GWAS study
1. These studies compare the DNA of participants having varying phenotypes for a
particular trait or disease.
2. Participants in a GWAS study may be people with a disease (cases) and similar
people without (controls), or they may be people with different phenotypes for a
particular trait, for example blood pressure. This approach is known as phenotype-
first, in which the participants are classified first by their clinical manifestation(s), as
opposed to genotype-first.
3. Each person gives a sample of DNA, from which millions of genetic variants are read
using SNP arrays. If one type of the variant (one allele) is more frequent in people
with the disease, the variant is said to be associated with the disease.
4. The associated SNPs are then considered to mark a region of the human genome
that may influence the risk of disease. In contrast to methods that specifically test
one or a few genetic regions, the GWA studies investigate the entire genome.
5. The approach is therefore said to be non-candidate-driven in contrast to gene-
specific candidate-driven studies. GWA studies identify SNPs and other variants in
DNA associated with a disease, but that cannot on their own specify which genes
are causal.

37. Highlights
•Can MR spectroscopy track metabolic changes in Parkinson's Disease?
•The study assesses the posterior cingulate cortex (PCC) and cognitive
impairment.
•There was no association with disease or cognitive ability at baseline or over
time.
•MR spectroscopy of PCC does not appear to be a useful clinical marker for
cognitive impairment in PD.
Proton Magnetic Resonance Spectroscopy (MRS), May
2007 and August 2013
N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and
myo-inositol (mI).

39. No finding MR ratio changes after
follow up 2-4 years
At baseline, relative to controls, PDD had significantly decreased NAA/Cr and
increased Cho/Cr.
At follow-up (2-4 years), no significant changes in MRS metabolite ratios were
detected

40. Highlights
•PD patients exhibit a distinctive serum miRNA profile from healthy controls.
•Five miRNA of 18 miRNA were identified to be differently expressed in PD
patients' serum.
•The 5-member serum miRNA panel can distinguish PD patients from health
individuals.
Up-regluated: miR-195
Down-regulated: miR-185, miR-15b, miR-221 and miR-181a
H. Ding et al. / Parkinsonism and Related Disorders 22 (2016) 68e73

41. miRNA might be a easier and specific
biomarkers.
H. Ding et al. / Parkinsonism and Related Disorders 22 (2016) 68e73

42. Highlights
•Orthostatic hypotension (OH) is common in Lewy body disorders (LBD).
•We identify a link between OH and hypoperfusion in parieto-occipital areas
using perfusion MRI.
•Supine hypertension (SH) was associated with hyperperfusion of frontal
regions.
•OH-defined parieto-occipital hypoperfusion relates to visuospatial-attention
deficits in LBD.
A.D. Robertson et al. / Parkinsonism and Related Disorders 22 (2016) 80e86
proof-of-concept study
N=15

43. Lower perfusion to temporal and
Occipital compared to a matched
small vessel disease.
Fig. 1. Regional cerebral blood flow (CBF) in Lewy
body spectrum disorder patients
(LBD) and non-demented adults with small vessel
disease (SVD). Scatter and error bar
plots of CBF in four cortical lobes. Regional CBF is
normalized to whole brain grey
matter (GM CBF). * indicates within-group
difference between regions corrected for
multiple comparisons (q ?0.05). Error bars reflect
mean ± standard deviation.
A.D. Robertson et al. / Parkinsonism and Related Disorders 22 (2016) 80e86

44. Highlights
•Depression is common in SCAs and depressive symptoms do not progress over 2
years.
•Suicidal ideation is more prevalent in SCA3.
•The effects of depression on ataxia progression vary across different SCA types.
•Depression has negative impact on functional status and quality of life in all SCAs,
after accounting for ataxia progression.
SCA 1, 2, 3 and 6 from Spinocerebellar Ataxias (CRC-SCA),
n=300 July 2009eMay 2012
R.Y. 88 Lo et al. / Parkinsonism and Related Disorders 22 (2016) 87e92
Classfication Prevalence of
depression
SCA1 24.5%
SCA2 20.3%
SCA3 25.2%
SCA6 17.8%

45. No association link between severity of depression and
motor progression follow up 2 years.
R.Y. 88 Lo et al. / Parkinsonism and Related Disorders 22 (2016) 87e92
unlike ataxia severity, depressive symptoms
do not seem to change over time or change along with the
motor disability, at least within the 2-year observation.